title: Neural correlates of rapid antidepressant response to ketamine in bipolar disorder.
abstract: OBJECTIVE
  Ketamine, an N-methyl d-aspartate (NMDA) antagonist, has rapid antidepressant effects in depressed subjects with bipolar disorder (BD). Evidence supports a role for the glutamatergic system in the pathophysiology of BD. This double-blind, randomized, cross-over study sought to determine cerebral metabolic correlates of antidepressant response to ketamine.
  
  
  METHODS
  Twenty-one subjects with BD currently in a depressed state underwent [(18) F]-fluorodeoxyglucose (FDG) positron emission tomography (PET) imaging after receiving a placebo infusion as well as after receiving a ketamine infusion. Metabolism was compared between ketamine and placebo infusions, and correlated with clinical response. Regional metabolic rate of glucose (rMRGlu) in regions of interest (ROIs) and Montgomery-Åsberg Depression Rating Scale (MADRS) scores were the main outcome measures.
  
  
  RESULTS
  The study found that change in metabolism between sessions was significantly correlated with percentage change in MADRS scores in the right ventral striatum; subjects who showed the greatest improvement had the largest metabolic increase after ketamine infusion compared to placebo. In a voxel-wise analysis, subjects with BD had significantly lower glucose metabolism in the left hippocampus following the ketamine infusion than following the placebo infusion. In addition, metabolism in the subgenual anterior cingulate cortex (ACC) following the placebo infusion was positively correlated with percentage improvement in MADRS score following the ketamine infusion.
  
  
  CONCLUSIONS
  Taken together, the results suggest that higher activity in the subgenual ACC may predict antidepressant response to ketamine. Ketamine administration altered glucose metabolism in areas known to be involved in mood disorders; these alterations may partially underlie ketamine's mechanism of action.
authors.affiliation: Experimental Therapeutics and Pathophysiology Branch, NIMH, NIH, Bethesda, MD, USA.
authors.forename: Allison C
authors.initials: AC
authors.lastname: Nugent
authors.forename: Nancy
authors.initials: N
authors.lastname: Diazgranados
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Carlson
authors.forename: Lobna
authors.initials: L
authors.lastname: Ibrahim
authors.forename: David A
authors.initials: DA
authors.lastname: Luckenbaugh
authors.forename: Nancy
authors.initials: N
authors.lastname: Brutsche
authors.forename: Peter
authors.initials: P
authors.lastname: Herscovitch
authors.forename: Wayne C
authors.initials: WC
authors.lastname: Drevets
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Zarate
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000928:Antidepressive Agents / Q000627:therapeutic use*; D001714:Bipolar Disorder / Q000145:classification / Q000188:drug therapy* / Q000473:pathology*; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000473:pathology; D001931:Brain Mapping; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007649:Ketamine / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D049268:Positron-Emission Tomography; D011569:Psychiatric Status Rating Scales; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000928:Antidepressive Agents; D007649:Ketamine
keywords: N-methyl d-aspartate (NMDA) antagonist; bipolar disorder; imaging; ketamine; positron emission tomography (PET)